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Review
. 2006 Oct;19(4):658-85.
doi: 10.1128/CMR.00061-05.

Molecular epidemiology of tuberculosis: current insights

Barun Mathema  1 , Natalia E Kurepina, Pablo J Bifani, Barry N Kreiswirth
Affiliations
Review

Molecular epidemiology of tuberculosis: current insights

Barun Mathema et al. Clin Microbiol Rev. 2006 Oct.

Abstract

Molecular epidemiologic studies of tuberculosis (TB) have focused largely on utilizing molecular techniques to address short- and long-term epidemiologic questions, such as in outbreak investigations and in assessing the global dissemination of strains, respectively. This is done primarily by examining the extent of genetic diversity of clinical strains of Mycobacterium tuberculosis. When molecular methods are used in conjunction with classical epidemiology, their utility for TB control has been realized. For instance, molecular epidemiologic studies have added much-needed accuracy and precision in describing transmission dynamics, and they have facilitated investigation of previously unresolved issues, such as estimates of recent-versus-reactive disease and the extent of exogenous reinfection. In addition, there is mounting evidence to suggest that specific strains of M. tuberculosis belonging to discrete phylogenetic clusters (lineages) may differ in virulence, pathogenesis, and epidemiologic characteristics, all of which may significantly impact TB control and vaccine development strategies. Here, we review the current methods, concepts, and applications of molecular approaches used to better understand the epidemiology of TB.

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Figures

FIG. 1.
FIG. 1.
Chromosomal maps of three M. tuberculosis strains: CDC1551 (http://tigrblast.tigr.org/cmr-BLAST/), H37Rv (http://genolist.pasteur.fr/TubercuList/index.html), and 210 (http://tigrblast.tigr.org/ufmg/index.cgi?database=m_tuberculosis-strain210%7Cseq). Arrows show the positions and orientations of IS6110 insertions. Left- and right-oriented arrows on the maps indicate IS6110 insertions, confirmed by insertion site mapping at the Public Health Research Institute Tuberculosis Center (unpublished data) and the positions of IS6110 according to Beggs et al. (18). The coordinates of the IS6110 insertions in all three strains correspond to the H37Rv annotated sequence. IS6110 mapping indicates that despite the insertion-preferential loci (“hot spots”), the precise positions (flanking sequences of the IS element) and orientations of the inserted sequences are not repeated in the three strains analyzed; i.e., none of the flanking regions of the four IS6110 copies in CDC1551 correspond to the 17 insertion sites in H37Rv or to the 23 positions (resulting in 21 hybridization bands) of the IS element in strain 210. The structures of the DR loci within these three strains are shown; black dots indicate spacers in the DR locus of corresponding strains, and triangles indicate deleted spacers. The chromosomal loci oriC and DR were described previously (137, 152, 167).
FIG.2.
FIG.2.
Representative genotypes superimposed on the SNP-derived phylogenetic framework of M. tuberculosis. Based on SNP analysis of M. tuberculosis clinical isolates (including 1,743 strains from Public Health Research Institute Tuberculosis Center strain collection), a phylogenetic tree with the nine clusters of M. tuberculosis isolates was used to illustrate common genotypic patterns (122). (A) IS6110-based RFLP images. (B) Spoligotype patterns (black dots show spacers present in the chromosomal DR region of strains, and open triangles indicate deleted spacers). The strain spoligofamily definition corresponds to the SpolDB4 (43). Cluster I includes M. tuberculosis complex strains and TbD1+ ancestral isolates. Cluster II is represented by the W-Beijing strain family, including strain 210. Cluster II.A comprises the CAS spoligotype isolates. Clusters I and II belong to PGG1, while II.A comprises both PGG1 and PGG2. The coclustering of isolates from PGG1 and PGG2 in cluster II.A is also shared by some spoligotypes (panel B). PGG2 is further delineated into clusters III, IV, V (including CDC1551), and VI, while PGG3 is represented by clusters VII and VIII (including H37Rv). Isolates with a single IS6110 insertion are found in clusters I, IIA, and IV. Likewise, some spoligotypes appear in more than one cluster. Similar/identical spoligopatterns may be found in unrelated strain clusters (e.g., “Beijing” spoligotypes in cluster VI or “Haarlem” spoligotypes in cluster VII) as a result of independent spacer deletion events; this convergence of spoligotypes could lead to the misinterpretation of genotyping results and illustrates the necessity of using two or more techniques in genotypic analysis. *, annotated laboratory strains (CDC1551 and H37Rv). (Adapted from reference with permission. © 2005 by the Infectious Diseases Society of America. All rights reserved.)
FIG.2.
FIG.2.
Representative genotypes superimposed on the SNP-derived phylogenetic framework of M. tuberculosis. Based on SNP analysis of M. tuberculosis clinical isolates (including 1,743 strains from Public Health Research Institute Tuberculosis Center strain collection), a phylogenetic tree with the nine clusters of M. tuberculosis isolates was used to illustrate common genotypic patterns (122). (A) IS6110-based RFLP images. (B) Spoligotype patterns (black dots show spacers present in the chromosomal DR region of strains, and open triangles indicate deleted spacers). The strain spoligofamily definition corresponds to the SpolDB4 (43). Cluster I includes M. tuberculosis complex strains and TbD1+ ancestral isolates. Cluster II is represented by the W-Beijing strain family, including strain 210. Cluster II.A comprises the CAS spoligotype isolates. Clusters I and II belong to PGG1, while II.A comprises both PGG1 and PGG2. The coclustering of isolates from PGG1 and PGG2 in cluster II.A is also shared by some spoligotypes (panel B). PGG2 is further delineated into clusters III, IV, V (including CDC1551), and VI, while PGG3 is represented by clusters VII and VIII (including H37Rv). Isolates with a single IS6110 insertion are found in clusters I, IIA, and IV. Likewise, some spoligotypes appear in more than one cluster. Similar/identical spoligopatterns may be found in unrelated strain clusters (e.g., “Beijing” spoligotypes in cluster VI or “Haarlem” spoligotypes in cluster VII) as a result of independent spacer deletion events; this convergence of spoligotypes could lead to the misinterpretation of genotyping results and illustrates the necessity of using two or more techniques in genotypic analysis. *, annotated laboratory strains (CDC1551 and H37Rv). (Adapted from reference with permission. © 2005 by the Infectious Diseases Society of America. All rights reserved.)
FIG. 3.
FIG. 3.
Distribution of M. tuberculosis SNP-derived clusters, based on patient country of origin. CEP, Columbia, Ecuador, and Peru; FIN, Finland; GEH, Guatemala, El Salvador, and Honduras; HDP, Haiti, Dominican Republic, and Puerto Rico; MEX, Mexico; PIB, Pakistan, India, and Bangladesh; SC, South Korea and China; USA, United States; VCP, Vietnam, Cambodia, and the Philippines. (Reprinted from reference with permission. © 2005 by the Infectious Diseases Society of America. All rights reserved.)
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